Background Amyloid imaging provides in vivo detection of the fibrillar amyloid-β (Aβ) plaques of Alzheimer's disease (AD). The positron emission tomography (PET) ligand, Pittsburgh Compound-B (PiB-C11), is the most well studied amyloid imaging agent, but the short half-life of carbon-11 limits its clinical viability. Florbetapir-F18 recently demonstrated in vivo correlation with postmortem Aβ histopathology, but has not been directly compared with PiB-C11.
Methods Fourteen cognitively normal adults and 12 AD patients underwent PiB-C11 and florbetapir-F18 PET scans within a 28-day period.
Results Both ligands displayed highly significant group discrimination and correlation of regional uptake.
Conclusion These data support the hypothesis that florbetapir-F18 provides comparable information with PiB-C11.
- Alzheimer's disease
- event-related potentials
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With the increasing potential of disease-specific therapeutic interventions, the search for non-invasive biomarkers of Alzheimer's disease (AD), pathology remains an active area of pursuit. Amyloid imaging, which provides an in vivo measurement of one of the hallmark pathological features of AD—fibrillar amyloid-β (Aβ) plaques—holds great promise in filling this role, and has already contributed significantly to our understanding of disease pathophysiology.1
The positron emission tomography (PET) ligand 11C-labelled Pittsburgh Compound-B (PiB-C11) is by far the most well studied amyloid imaging agent. In addition to reliably differentiating patients with AD from healthy controls, and predicting the likelihood of progression to AD in patients with mild cognitive impairment (MCI),2–8 strong correlations with histological measures of Aβ aggregates have been observed.9–12 However, because of the short half-life of carbon-11 (∼20 min), PiB-C11 PET has limited potential for use outside of the research setting.
Fluorine-18-labelled PET ligands allow for more general clinical use due to their longer half-life (∼110 min). Several fluorine-18 amyloid imaging agents are in varying degrees of development.13–15 Similar to PiB-C11 PET, florbetapir-F18 has demonstrated in vivo correlation with postmortem histopathology, is currently being utilised in the Alzheimer's Disease Neuroimaging Initiative (ADNI), as well as other clinical intervention trials, and was recently approved by the US Food and Drug Administration (FDA) for clinical use in the USA. Given the wealth of experience with PiB-C11 PET, an improved characterisation of the correspondence between florbetapir-F18 and PiB-C11 PET would assist with interpretation of these studies. To examine the overlap of the two ligands, we obtained PET scans with both agents in patients with AD and cognitively normal (CN) controls.
Fourteen patients with AD (age: 69±10 (SD) years; MMSE: 22±4.6 (SD); 12 females); and 15 CN adults (age: 71±9 (SD) years; MMSE: 30±0.5 (SD); 8 females) participated in the study. All participants were recruited from the cohort of the University of Pennsylvania's Alzheimer's Disease Center (ADC). As part of enrolment in the ADC, an extensive annual evaluation is performed, including medical history and physical examination, neurological history and examination, semistructured psychiatric evaluation, and neuropsychological assessment; including all components of the National Alzheimer's Coordinating Center's (NACC) Uniform Data Set (UDS; (24–26)). Clinical diagnosis is determined at a consensus conference attended by neurologists, neuropsychologists, geriatricians and psychiatrists.
Diagnosis of AD was made according to the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria.16 CN adults were defined as an absence of significant cognitive complaints, normal performance on age-adjusted cognitive measures, and consensus conference designation as ‘normal.’ Inclusion criteria included age between 55 and 90, fluency in English, and Mini-Mental State Examination (MMSE) score between 18 and 26 for AD and ≥27 for CN adults. Participants were excluded if they had a history of another significant neurological condition, such as clinical stroke, alcohol or drug abuse/dependence within 2 years of enrolment, any significant medical/psychiatric condition that would impact compliance with the study protocol, current participation in any amyloid-specific therapeutic trial, or prior involvement in an immuno-based clinical trial for AD. The study was approved by the Institutional Review Board of the University of Pennsylvania.
Neuroimaging acquisition and analysis
PET imaging was performed on an Allegro whole-body PET scanner (Phillips). PiB-C11 PET and florbetapir-F18 PET were acquired on either the same day or two separate days separated by no more than 28 days. If performed on the same day, at least 120 min (∼6 half-lives of PiB-C11) must have passed between injection of PiB-C11 and florbetapir-F18. PiB-C11 PET imaging followed the ADNI protocol. Dynamic 3-D imaging for 20 min (4×5-min frames) began 50 min following bolus intravenous injection of 555 MBq (15±1.5 mCi) PiB-C11. Florbetapir-F18 PET imaging was conducted as previously described.14 Dynamic 3-D imaging for 10 min (2×5-min frames) began 50 min following bolus intravenous injection of 370 MBq (10±1.0 mCi) florbetapir-F18. Due to technical failures, one AD patient and CN adult did not complete the PiB-C11 PET scan, while one AD patient did not complete the florbetapir-F18 scan.
The multiple frames of each image were averaged and normalised to a tracer-specific (PiB-C11 or Florbetapir-F18) PET template in Talairach space using SPM 2 (these were standard templates, previously derived by averaging scans from both CN and AD subjects from other studies with the respective tracers). Standardised anatomical regions of interest (ROI) were chosen based on typical association with amyloid plaque deposition2 ,17 and applied to the PET image in template space.14 These ROIs included: anterior cingulate, posterior cingulate/precuneus, frontal cortex, parietal cortex, lateral temporal cortex, pons and whole cerebellum. Given the general symmetry of PiB-C11 uptake,18 ROIs were averaged across the right and left hemispheres. A composite ROI was also generated from the above cortical regions. Standardised uptake values (SUVs), calculated as the integrated activity over a given time period per unit of injected dose and body weight, were determined. ROIs were then referenced to the whole cerebellum to calculate standardised uptake value ratios (SUVR6 ,14).
Pearson correlation coefficient (r) was used to determine the correlation between the florbetapir-F18 and PiB-C11 SUVR values. The receiver operating characteristic curve of cortical SUVR for classification of subjects as AD or NL was derived for both ligands. In addition, two sample t tests were used to compare SUVR values between the two cohorts for each ligand separately.
SUVRs for individual and composite ROIs are presented in table 1. Both ligands displayed significantly higher uptake in the AD relative to the CN group in ROIs that are generally associated with amyloid plaque deposition in AD (p<0.05).2 ,17 A composite measure of these regions was highly significant in group discrimination for both, florbetapir-F18 (AUC=0.90, 95% CI 0.77 to 1.00) and PiB-C11 (AUC=1.00). Neither ligand displayed a group difference in the pons (p>0.1), a region in which uptake would be expected to be nonspecific (figure 1A).
SUVRs for all the cortical ROIs were highly correlated between the two methodologies (r=0.58–0.81; see table 1). Interestingly, the ROI with the weakest correlation, parietal cortex (r=0.58), was also the cortical ROI that displayed the smallest group difference. Consistent with the individual ROIs, the composite cortical ROI was highly correlated across the two ligands (r=0.78, p<0.001), but the range of SUVRs was greater with PiB-C11 PET (figure 1B).
The development of fluorine-18 PET amyloid imaging ligands that reliably detect AD-related amyloid plaque pathology has the potential to greatly expand the ability to use these methodologies in research and clinical practice. The current study examined the relationship of one of the most developed of these compounds, florbetapir-F18. In vivo imaging with this compound has already demonstrated significant correlation with histological findings on autopsy.14 This is the first published study directly comparing this agent with PiB-C11 in the same patients within a short temporal interval (<28 days).
We found very similar and robustly correlated binding characteristics for the two compounds. Both PET ligands displayed excellent ability to discriminate CN adults from those with mild AD. Further, there was no evidence of group differences in the degree of nonspecific binding in the pons, a region not associated with fibrillar amyloid pathology. While fluorine-18-labelled amyloid imaging agents, such as florbetapir and other newer ligands (eg, flutemetamol-F18), generally have been associated with higher white matter uptake,15 ,19 SUVRs for the pons were similar for the two ligands. However, florbetapir-F18 uptake in the pons was relatively higher in relation to cortical regions compared with that observed for PiB-C11. Nonetheless, all regions displayed highly significant correlation across the two methodologies, providing additional support that these ligands have very similar binding characteristics.
Despite this overlap, there were some differences. Although there was a strong correlation between the methods, the range of SUVRs between the lowest and highest values was larger for the PiB-C11 PET scans (see figure 1B). Second, while both compounds clearly distinguished the two populations, there was less overlap with PiB-C11 PET, based on the receiver operating characteristic analysis (see table 1). One potential explanation for this is the greater relative nonspecific white matter uptake of florbetapir-F18 relative to cortical uptake. Particularly in the context of the grey matter atrophy associated with AD, inclusion of some white matter signal in cortical ROIs is likely, and could result in reduced specificity of the findings.
However, comparison of the two compounds to discriminate, based on clinical status, should be viewed with caution given the frequent finding of amyloid plaque pathology in CN individuals.20 Since we do not have the ‘gold standard’ of histological confirmation, it is possible that at least some of the overlap between CN adults and those with AD of florbetapir-F18 PET uptake may reflect sensitivity to this ‘preclinical’ pathology. Indeed, Joshi et al suggested an SUVR cut-off of 1.10 for establishing a positive florbetapir scan21; the sensitivity and specificity of this cut-off for detecting patients with moderate to frequent neuritic plaques at autopsy has been recently confirmed.22 If the regression line (figure 1B) is used to impute the comparable cut-off point for PIB (SUVR =1.15), all the CN subjects identified as amyloid positive by florbetapir would also be identified as amyloid positive by PIB.
While the present data do not allow us to directly determine which of the present subjects were truly amyloid positive, it is possible to compare the PET results for some of these subjects with an independent amyloid biomarker; eight individuals in this study (3 CN; 5 AD) also had cerebrospinal fluid (CSF) levels of Aβ1–42 obtained within 1 year of their scan (mean: 72 days). Previous work at the University of Pennsylvania, including an autopsy series, has established a cut-off for Aβ1–42 (<192 pg/ml) with 96% sensitivity to underlying AD-related amyloid pathology.23 Based on this cut-off, all the AD subjects with low (amyloid positive) CSF Aβ1–42 values (grey crosses in figure 1B) were clearly elevated in PiB uptake. While two of these AD patients had florbetapir uptake in the CN range, both were above the above-noted threshold of an SUVR of 1.10 (1.12–1.17). Two CN adults (black crosses in figure 1B) displayed evidence of amyloid pathology by CSF. Interestingly, one of these adults was within the low range of PET uptake for both compounds, which was inconsistent with the CSF Aβ1–42 result. The other CN adult with an abnormal CSF had the second highest composite PiB SUVR value of the CN participants, and was in the AD range for florbetapir-F18, suggesting that at least some of the overlap in the clinical groups may be due to CN adults harbouring amyloid pathology.
Finally, there was also some variability in the correlation of the two measures in particular regions, such as the parietal cortex. The reason for this is unclear, but it could be due to the fact that this is a region with significant atrophy in AD and, thus, more susceptible to local nonspecific white matter uptake. Alternatively, differential binding of the two compounds to different species of fibrillar amyloid is possible, and merits further investigation.
Overall, we found a high correlation between the binding properties of florbetapir-F18 and PiB-C11 PET, supporting the hypothesis that these agents provide generally analogous information. The present results echoe the findings with flutemetamol-F18 PET, essentially fluorine-18-labelled PiB, which displayed similar correlations with PiB-C11 PET.19 Taken together, these findings suggest a role for the more accessible fluorine-18 amyloid imaging ligands in clinical research studies. Furthermore, research data with PiB-C11 PET can be used to inform clinical experience now that florbetapir-F18 PET has been approved for use by the FDA in the USA.
Funding This study was supported in its entirety by the Pennsylvania Department of Health (#4100037703).
Competing interests Dr Wolk has received consulting fees from GE Healthcare, Inc. Drs Clark and Pontecorvo owned Avid stock and/or stock options and are employed by Avid Radiopharmaceuticals Inc, a wholly owned subsidiary of Eli Lilly and Company.
Ethics approval Ethics approval was provided by University of Pennsylvania Institutional Review Board.
Provenance and peer review Not commissioned; externally peer reviewed.
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